Abstract
The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.SIGNIFICANCE STATEMENT The glymphatic system contributes to the removal of amyloid β from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.
Highlights
While Alzheimer’s disease (AD) is the most common cause of dementia, at least 15 million people worldwide currently sufferReceived July 31, 2018; revised March 31, 2019; accepted May 30, 2019
As arterial pulsation is a driver of this CSF-interstitial fluid (ISF) exchange (Iliff et al, 2013b; Mestre et al, 2018a), and since arterial distensibility is reduced in chronic hypertension (Baumbach and Heistad, 1988), we hypothesize that the CSF-ISF exchange is reduced in an animal model of essential hypertension, spontaneously hypertensive (SHR)
We found no significant difference in subarachnoid CSF volume surrounding circle of Willis (CoW), but subarachnoid CSF volume was significantly lower in basal brain stem
Summary
While Alzheimer’s disease (AD) is the most common cause of dementia, at least 15 million people worldwide currently suffer. Received July 31, 2018; revised March 31, 2019; accepted May 30, 2019. From dementia arising wholly or in part from small vessel disease (SVD) of the brain. Vascular pathologies, including hypertension, are risk factors for AD (Hachinski, 2015). SVD is common in patients with chronic hypertension, and can progress silently. Neurosci., August 7, 2019 39(32):6365– 6377 a bb
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